Randomized phase II study of daily and alternate-day administration of S-1 for adjuvant chemotherapy in completely-resected stage I non-small cell lung cancer: results of the Setouchi Lung Cancer Group Study 1301

Lung cancer is the most common cause of cancer-related death worldwide [1]. Surgery is considered to be the primary treatment modality for early stage non-small cell lung cancer (NSCLC) and the 5-year overall survival (OS) rates are 88.9 and 76.7% for pathological stage IA and IB NSCLC patients, respectively [2]. However, 15% of patients with stage IA NSCLC develop distant metastases even after complete resection [3].

A series of randomized controlled trials, including ANITA, JBR10, and CALGB9633, as well as the LACE meta-analysis, failed to demonstrate an OS benefit of platinum-based chemotherapy following complete surgical resection of pathological N0 NSCLC [4‐7].

In Japan, however, a series of randomized phase III trials suggested a survival benefit for adjuvant chemotherapy with the oral drug uracil-tegafur (UFT) in patients with pathological N0 NSCLC following complete resection [8‐10]. Meta-analysis by Hamada et al. revealed that UFT was beneficial for patients with a tumor size > 2 cm [11]. On the basis of these findings, the Japanese Lung Cancer Practice Guidelines, which were developed by the Japanese Society of Lung Cancer, recommended UFT therapy in completely resected N0 NSCLC patients with a tumor size > 2 cm for up to 2 years (https://​www.​haigan.​gr.​jp/​modules/​guideline/​index.​php?​content_​id=​3). Furthermore, a recent randomized phase III trial conducted by our group demonstrated that no survival difference was observed between UFT versus paclitaxel plus carboplatin as adjuvant chemotherapy for completely resected stage IB to IIIB NSCLC [12].

S-1 (TS-1; Taiho Pharmaceutical Co., Ltd., Tokyo, Japan) is an oral fluoropyrimidine agent consisting of tegafur (a prodrug of 5-fluorouracil [5-FU]), gimeracil (an inhibitor of dihydropyrimidine dehydrogenase, which degrades fluorouracil), and oteracil, which inhibits the phosphorylation of fluorouracil in the gastrointestinal tract, thereby reducing the gastrointestinal toxic effects of fluorouracil, in a molar ratio of 1:0.4:1 [13]. S-1 was developed to improve the tumor-selective cytotoxicity of 5-FU, reduce gastrointestinal toxicity, and provide a higher antitumor effect compared with UFT. A phase II trial of S-1 monotherapy as first-line treatment for patients with advanced NSCLC resulted in a 22% response rate [14]. Regarding the adjuvant setting, S-1 adjuvant chemotherapy following curative surgery improved OS in gastric cancer or pancreatic cancer in phase III trials [15, 16]. Additionally, in a randomized phase III study, adjuvant chemotherapy with S-1 after curative treatment in patients with head and neck cancer revealed that OS was significantly greater in the S-1 group compared with that in the UFT group [17]. As for NSCLC, some phase II studies for resected NSCLC demonstrated the feasibility and efficacy of S-1 based adjuvant chemotherapy [18‐21].

Recently, Kunitoh et al. reported the results of a phase III study that evaluated the efficacy of S-1 compared with UFT for post-operative adjuvant chemotherapy of node negative NSCLC. However, they were unable to demonstrate superiority of adjuvant S-1 therapy over UFT with respect to relapse-free survival (RFS) [22]. They suggested that one reason for the lack of superiority was that the outcomes of patients in the trial were exceedingly good for both arms and that future investigation should incorporate identification of, and be focued on, the high-risk populations for recurrence.

The original schedule for S-1 was a 4 week administration followed by a 2-week rest period for 1 year (conventional schedule) and the feasibility of administering S-1 according to this conventional schedule has been previously confirmed in patients with completely resected NSCLC [18, 23]. However, the discontinuation or dose reduction of S-1 often occurs because of adverse events during the conventional treatment schedule. To decrease the toxicity of S-1, a modified schedule has been used in which S-1 is administered for 2 weeks followed by a 1-week rest period (modified schedule) for patients receiving treatment according to the conventional schedule that experience severe toxicities [24].

A randomized scheduling feasibility study for S-1 has shown that the modified schedule appears to be more feasible compared with the conventional schedule in locoregionally advanced squamous cell carcinoma of the head and neck [25]. In our previous phase II study comparing the conventional and modified schedules of S-1 administration in patients with completely resected pathological stage IA (tumor diameter, 2–3 cm) NSCLC, we could not demonstrate a significant difference in feasibility between the two groups. However, we demonstrated that grade 3/4 toxicities were significantly less frequent in patients treated with the modified schedule compared with the conventional schedule despite equivalent survival for both groups [26]. As a result, the modified S-1 administration schedule has become more popular in clinical practice.

To further reduce the incidence of drug-induced adverse effects and improve the feasibility of administration, an alternate-day S-1 schedule has recently been investigated. The alternate-day regimen of S-1 was safer and more tolerable compared with the daily regimen in patients with gastric, pancreatic, and head and neck cancer [27‐29]. In recent reports, an alternate-day administration of S-1 was also demonstrated to be a potentially safe treatment regimen for elderly patients with advanced NSCLC [30]. To our knowledge, however, there are no reports of prospective studies using an alternate-day S-1 administration of adjuvant chemotherapy for completely resected NSCLC.

Therefore, we conducted a multicenter, randomized phase II trial comparing the feasibility and safety of alternate-day administration of S-1 versus daily administration for 2 weeks followed by a 1-week rest period as adjuvant chemotherapy in completely resected stage I (tumor diameter > 2 cm) NSCLC.

The cell cycle period of normal cells is shorter than that of tumor cells (0.5–1 day versus 3–7 days, respectively) and the duration of the S-phase in tumor cells is ≥1 day. 5-FU exhibits activity toward S-phase cells by inhibiting DNA synthesis and cell proliferation. Shirasaka et al. recommended the use of an alternate-day schedule for S-1 administration instead of daily use based on the observation that the former would provide time for the recovery of normal epithelial cells in the gastrointestinal tract and bone marrow while still maintaining an anticancer effect [33]. Using gastric cancer cell lines in vitro and in vivo, a previous study showed that alternate-day S-1 administration was associated with lower toxicity while yielding a similar antitumor effect compared with standard daily administration [34]. Moreover, a retrospective study showed that alternate-day S-1 administration was associated with reduced adverse events compared with standard daily S-1 administration in patients with advanced gastric cancer [35]. In a randomized phase II trial for patients with advanced NSCLC, Suzuki et al. demonstrated that the alternate-day administration of S-1 was less toxic and did not compromise its therapeutic effectiveness compared with the standard daily administration of S-1 [36].

In the present study, we compared alternate-day administration of S-1 with daily administration for 2 weeks followed by a 1-week rest in an adjuvant setting for completely resected stage I (T > 2 cm) NSCLC. In an analysis of a phase III study of postoperative gastric cancer [15], when the protocol completion cases were divided into two groups according to compliance with S-1 administration, the 5-year survival curves overlapped for patients with ≥90% RDI and patients with 70 to < 90% RDI (in-house experimental data; Taiho Pharmaceutical). Therefore, we concluded that an RDI of 70% provides sufficient adjuvant chemotherapy for NSCLC with S-1, similar to gastric cancer. A treatment completion rate of 6 months with an RDI of 70% or more in the alternate-day administration group was over 60% (86.7%) and exceeded that in the daily administration group by more than 15% (22.3%). On the basis of this result, an alternate-day administration of S-1 appears to be feasible and promising for adjuvant chemotherapy in completely resected stage I NSCLC.

In an adjuvant setting, low toxicity is a particularly important factor because postoperative frail patients are likely to be overcome with toxicity and treatment discontinuation resulting from toxicity may attenuate the effectiveness of adjuvant chemotherapy. As a result, alternate-day administration of S-1 would be a good candidate for adjuvant chemotherapy. As for alternate-day administration of S-1, fewer studies on adjuvant chemotherapy have been reported compared with that of chemotherapy for advanced cases. Prospective studies of alternate-day S-1 as adjuvant chemotherapy for gastric cancer and head and neck cancer demonstrated improved feasibility, low toxicity, and efficacy [28, 37]. The current study demonstrated that alternate-day administration of S-1 for adjuvant chemotherapy in NSCLC was also feasible and exhibited low toxicity with an acceptable survival rate.

In the phase III study by Kunitoh et al., S-1 was not superior to the efficacy of UFT in the same population as our study. They administered S-1 daily for 2 weeks followed by a 1-week rest for 1 year. The dose reduction rate resulting from treatment toxicity was 40.3% in the S-1 arm compared with 20.1% in the UFT arm and there were three treatment-related deaths in the S-1 arm [22]. If an alternate-day S-1 administration is adopted, the feasibility and safety of the S-1 arm may be improved while enhancing the effectiveness of the adjuvant chemotherapy. Therefore, our results that demonstrated to be feasible with low-toxicity of alternate-day S-1 administration as adjuvant chemotherapy in resected stage I NSCLC is considered to have a significant clinical implication irrespective of the results of the phase III study by Kunitoh et al.

In addition, the primary endpoint of the Kunitoh study, 5-year RFS, was 79.5% in the S-1 arm compared with 79.4% in the UFT arm. The treatment duration was 1 and 2 years in the S-1 and UFT arms, respectively. Considering a similar efficacy for both arms, short duration adjuvant chemotherapy with S-1 may be advantageous compared with UFT therapy.

This study had some limitations. The weaknesses of our study design included the lack of pill counts. Drug compliance may be an important challenge in this study. In addition, information of driver mutation other than EGFR or programmed cell death-ligand 1 (PD-L1) were not collected in this trial. We also did not investigate outcome according to stratification by patient age. A previous study of adjuvant chemotherapy with S-1 according to a conventional daily schedule demonstrated that the RDI of patients over 65 years old was significantly lower compared with that of the other patients. Additionally, the conventional daily administration of S-1 was not likely to be feasible in elderly patients with completely resected NSCLC [22]. However, our group is now conducting a randomized phase II trial to confirm the advantage of alternate-day S-1 administration compared with daily S-1 administration as adjuvant chemotherapy for elderly NSCLC patients (UMIN000007819).

Alternate-day oral administration of S-1 was demonstrated to be feasible with low-toxicity as adjuvant chemotherapy in completely resected stage I (tumor diameter > 2 cm) NSCLC. These results are promising and warrant a subsequent phase III study of alternate-day administration of S-1 compared with the standard care for these patients, which should be incorporate identification of, and be focued on, the high-risk populations for recurrence according to the results of JCOG0707.